The accumulation of beta-amyloid peptides (Abeta) in the brain plays a key role in Alzheimer's disease (AD). Inflammatory responses of glial cells may also be involved, but their role appears to be complex, with some responses protecting and others damaging the brain. To harness microglial activities therapeutically, one must first identify the mediators of their beneficial functions. Recent reports suggest that immunization with Abeta can prevent and partially reverse AD-like brain alterations in transgenic mouse models, possibly by activating anti- amyloidogenic functions of microglia. Those studies focused on amyloid plaques and were not designed to dissect the underlying molecular mechanisms. Our studies of human amyloid protein precursor (hAPP) transgenic mice suggest that AD-related synaptic/neuronal dysfunction and degeneration are caused by nondeposited forms of Abeta. Such plaque-independent neuronal deficits were inhibited by human apolipoprotein (apo) E3, but not by apoE4, the best established genetic risk factor for the most common form of AD. Here we will assess whether Abeta vaccination can inhibit plaque-independent neurodegeneration and cognitive impairments, and whether it can do so even in the high-risk environment created by apoE4. Using hAPP and hAPP/apoE transgenic mice, we will determine whether Abeta vaccination prevents, inhibits, or reverses loss of presynaptic terminals and cholinergic neurons (Aim 1) and deficits in spatial and nonspatial learning and memory (Aim 2). Since the processes underlying the therapeutic effects of Abeta vaccination may be reflected in changes in gene expression, we will also use DNA microarrays to compare the gene expression profiles of specific brain regions and plaque-associated microglia in transgenic mice that have or have not been immunized with Abeta (Aim 3). We will then determine whether the genetic or pharmacological manipulation of specific microglial gene products diminishes or augments the therapeutic effect of Abeta vaccination (Aim 4). These studies will significantly expand the preclinical evaluation of Abeta vaccination with respect to AD-related neurodegeneration and cognitive impairment. They will also advance our understanding of the processes that underlie the therapeutic effects of this novel treatment, and thereby facilitate its optimization. Lastly, the proposed project will shed light on the roles of microglia in the pathogenesis of AD-related neuronal deficits. These goals and perspectives are congruent with those of RFA AG-01-003.